# Isoform-Selective AMPK Agonists for Treating Subtypes of Mitochondrial Disease

> **NIH NIH R43** · EVVIA THERAPEUTICS, INC. · 2021 · $350,000

## Abstract

ABSRACT
Mitochondrial diseases are a clinically heterogenous group of orphan disorders caused by electron transport
chain (ETC) dysfunction and associated with degenerative symptoms affecting single organ or multisystem
function. There is no effective treatment or cure and no FDA-approved drug for any of these devastating
disorders. To identify and characterize potential therapeutic compounds, we developed an in vitro screening
assay and identified direct AMP-activated protein kinase (AMPK) activators originally explored for the treatment
of diabetes and metabolic syndrome. Unlike previously investigated AMPK agonists such as 5-
Aminoimidazole-4-carboxamide ribonucleotide (AICAR), these compounds allosterically activate AMPK in an
AMP-independent manner, thereby increasing specificity and decreasing pleiotropic effects. We showed that
direct AMPK activators significantly improve mitochondrial function, energy status, and cellular redox of
fibroblasts isolated from patients with mitochondrial disease. We also showed that they protected against
retinal degeneration and improved muscle weakness in a mouse model of mitochondrial dysfunction, further
supporting the therapeutic potential of direct AMPK agonists in the treatment of mitochondrial diseases. While
direct AMPK agonists proved effective in reducing organ damage caused by mitochondrial dysfunction,
activating AMPK broadly across tissue also resulted in cardiac hypertrophy. In order to improve tissue
selectivity and reduce off-target tissue effects associated with pan-AMPK activation, we developed a class of
proprietary AMPK activators that selectively activate AMPK isoforms highly expressed in human eye tissue.
These selective agonists will be valuable in treating Leber's Hereditary Optic Neuropathy (LHON), a subtype of
mitochondrial disease characterized by severe vision loss that leads to blindness mostly in teens and young
adults. We formed Evvia Therapeutics as a result of this promising academic research and now seek to verify
the pharmacological safety properties of the proprietary agonists through both in vitro and in vivo ADME-Tox
assessments. We also seek to evaluate the efficacy of our agonists using a mouse model of LHON in
preparation for IND-enabling studies.
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## Key facts

- **NIH application ID:** 10252080
- **Project number:** 1R43EY032886-01
- **Recipient organization:** EVVIA THERAPEUTICS, INC.
- **Principal Investigator:** Tereza Moore
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $350,000
- **Award type:** 1
- **Project period:** 2021-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10252080

## Citation

> US National Institutes of Health, RePORTER application 10252080, Isoform-Selective AMPK Agonists for Treating Subtypes of Mitochondrial Disease (1R43EY032886-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10252080. Licensed CC0.

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